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Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

Elizabeth L GuentherQin CaoHamilton TrinhJiahui LuMichael R SawayaDuilio CascioDavid R BoyerJosé A RodriguezMichael P HughesDavid S Eisenberg
Published in: Nature structural & molecular biology (2018)
The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation.
Keyphrases
  • amyotrophic lateral sclerosis
  • binding protein
  • high resolution
  • endothelial cells
  • gene expression
  • stress induced
  • dna methylation
  • heat stress
  • amino acid
  • single molecule
  • copy number
  • nucleic acid